Efficacy and safety of oral immunotherapy for peanut, cow's milk, and hen's egg allergy: A systematic review of randomized controlled trials

Abstract Background Oral immunotherapy (OIT) is a promising treatment for food allergies; however, safety is a concern. We synthesized evidence from the best randomized controlled trials (RCTs) on efficacy/safety of OIT for desensitization (DS) and remission (sustained unresponsiveness (SU)) in IgE mediated allergy to peanut, hen's eggs, and cow's milk. Body We searched Pubmed, EMBASE, and Cochrane databases (Until Oct 22) identifying 16 eligible RCTs published in English measuring food allergy by food challenge at the beginning and at the end of the study. The Cochrane Risk of Bias tool was used to assess study quality. We found 18 eligible studies. There was evidence of efficacy for DS for all allergens: peanut (RR 11.32; 95% CI 5.93, 21.60, I 2 49%, 8 studies); hen's egg (RR 4.67; 2.66, 8.21, I 2 0%, 5 studies); cow's milk (RR 13.98; 3.51, 55.65, I 2 0%, 4 studies) and evidence for SU for peanut (RR 7.74; 2.90, 20.69, I 2 0%, 3 studies) and hen's egg (RR 6.91; 1.67, 28.57, I 2 0%, 2 studies). Allergic events were increased with intervention, and risk of adrenaline use increased for peanut RR 2.96; 1.63, 5.35, I 2 0%, 8 studies; egg RR 1.71; 0.42, 6.92, I 2 0%, 6 studies; and milk RR 8.45; 2.02, 35.27, I 2 0%, 4 studies. Conclusion We found strong evidence that peanut, hen's egg, and cow's milk OIT can induce DS and some evidence for remission. There was a high risk of allergic reactions. Generalizability to the entire food allergic population is not known.


| INTRODUCTION
IgE-mediated food allergy affects up to ten percent of 12-month old children 1 and has a significant impact on quality of life (QoL) of the child and their family. 2 Egg, milk, and peanut allergies are among the most common food allergies. 3 The causes of food allergy remain poorly understood; however, there is evidence that early introduction of allergenic foods may help prevent the development of food allergy. 4,5 Current management of established food allergies includes strict allergen avoidance and early management of reactions to accidental ingestion. In practice, total avoidance is difficult and most children experience multiple episodes of ingestion. 6 Food avoidance impacts the quality of life of the child and their family. 7 Finding a 'cure' for food allergy remains a high priority.
Food allergen immunotherapy is receiving increased interest as a potential treatment. To date, the most promising method is oral immunotherapy (OIT). 8,9 OIT regimens vary but usually involve three phases: initiation, escalation, and maintenance. In practice, this means ingestion of food allergens starting from a very small amount (initiation) and incrementally increasing over a defined period (escalation) until a target dose is achieved and maintained (maintenance). Outcomes of OIT are usually measured as desensitization (DS) and sustained unresponsiveness (SU) (remission). 10 DS describes increase in reaction threshold, that is, the amount of allergen able to be orally ingested without reaction. It is a temporary state maintained with continued allergen exposure 11 typically daily. Remission describes lack of clinical reactivity which is maintained for a time despite discontinuing allergen ingestion and is indicative of a longer lasting change. There is no consensus on the time required without allergen intake to define remission but periods between 2 weeks and 6 months have been applied in published studies. 10 The main concerns regarding OIT are the potential for frequent/ daily OIT doses to cause life-threatening allergic reactions [12][13][14] and uncertainty about impact on quality of life (QoL). There is also continued uncertainty about the potential for and rate of long-term remission from these therapies. Improved understanding of OIT risks and benefits 15 and whether it leads to improved QoL remains to be confirmed. 16,17 Several systematic reviews have addressed OIT as a treatment for peanut, egg, and/or milk allergy. 12 focussed on egg OIT. It comprised 10 RCTs of OIT for eggs and did not report outcomes of desensitization to a fixed dose or sustained unresponsiveness, instead reporting any tolerance to a part amount or a "serving size". A more recent OIT systematic review of RCTs published in the Lancet focused only on peanut. 12 It comprised 12 trials but included 5 which had not measured peanut allergy by OFC at baseline and 1 using sublingual immunotherapy as the control. In 2022, 3 new systematic reviews were published [20][21][22] with varying findings for the efficacy of OIT.
Although informative, none of these reviews have been limited to the best evidence, namely good quality RCTs where food allergy was established objectively by oral food challenge (OFC) at the beginning and end of the trial for both the intervention and control groups, and intention-to-treat (ITT) analyses reported. It is critical to limit to best quality RCTs to obtain accurate information concerning efficacy and safety to provide the most unbiased estimates of the risks and benefits of using these treatments. We aimed to review the current best evidence from RCTs for the effectiveness of peanut, egg, and cow's milk OIT on desensitization and remission and adverse allergic events.

| Search strategy
PubMed, EMBASE and Cochrane databases searched from inception for peer-reviewed English publications (Tables S1-S3). PROSPERO systematic review registry (No: CRD 42018099929). Last search Oct 2022.

| Inclusion criteria
RCTs, published in English, investigating OIT efficacy for OFC-proven IgE mediated food allergy to peanut, egg, or milk. Intervention: OIT.
Comparison: placebo or food avoidance.
Included studies were required to have outcomes of desensitization (DS) and/or sustained unresponsiveness (SU) (terminology used in included studies for remission) in humans, to have OFC on all participants prior to commencement and on study completion. ITT reported or able to be calculated. 1. Desensitization (DS) is defined as increase in reaction threshold for allergens.

Sustained Unresponsiveness (SU) is defined as a lack of clinical
reactivity maintained for at least 2 weeks despite allergen discontinuation.
3. Adverse reactions are any reported adverse reactions in either placebo or treatment groups.

| Selection of studies
After the removal of duplicates, studies identified were independently screened by two authors (NW, CL). Full-texts were then read by the same authors to determine suitability for inclusion. Any disagreements were settled by a third author (SD). Endnote and Covidence were used.

| Data extraction
Using a standardized form, data were extracted independently by 2 authors (NW, MN, JB or CL). We extracted trial details: (first author; year published; country; number and age of participants; duration; how food allergy defined, consideration of baseline reaction threshold; outcomes and their definitions; confounding and moderating factors, numbers (proportions) achieving DS/SU in the treatment and control arms (ITT)); details of immunotherapy: (starting dose; dose escalation; final dose; length of treatment; need for hospitalization/observation as part of regime and any immunomodulatory therapies added) and adverse effects (any vs. no reactions per child (trials with placebo); and use of parenteral adrenaline for intervention versus control (placebo or avoidance)).

| Quality assessment/risk of bias
Assessed independently by 2 authors (XD or CL) using the Cochrane risk of bias tool for RCTs.

| Statistical analysis
Associations from individual studies expressed as proportions achieving DS and SU were converted to risk ratios and 95% CIs and pooled in random effects (inverse-variance model) meta-analyses for individual allergens (peanut, egg, and milk). I 2 statistic was used to assess heterogeneity with values >75% considered high. 23 Effect estimates for adverse reactions pooled. All analyses used Stata/SE 17.0.
We calculated the number needed to treat (NNT) for DS, SU, and allergic adverse events as per Cochrane methods. NNT = 1/[(RR-1) x risk in control group] for RR > 1 and, NNT = [1/(1-RR) x risk in the control group] for RR < 1. 23 The assumed control risk (ACR) was calculated from the numbers in the included studies.

| Role of funding source
The funder had no role in the study design, collection, analysis, or interpretation of the data nor in the decision to submit for publication.

| Overview of studies
The eight peanut RCTs 11,26-32 included 1414 participants in total with numbers varying between 56 29 and 555 32 participants. One study was conducted in the UK, 28 one in Germany, 30 three in the USA, 11,27,29 two in multi-country sites 31,32 (Europe and US) and one in Australia (Table 1). 26 Participant age ranged from a mean of 3.1 27 -12.4 years. 28 Age inclusion criteria varied with four studies 28,30,31 including participants up to 16 or 17 years and two 11,29,32 up to 21 years. Four studies 26,27,29,31 excluded children with previous life threatening or severe anaphylaxis and seven studies 11,26-31 excluded children with severe or poorly controlled asthma. Importantly, five of the studies 11,26,29,30,32 provided detailed information on the reasons screened participants were not included in the studies. Of the 1495 people screened in these 5 studies, 205 (14%) were excluded because they were tolerant of peanut on the initial DBPCFC (Table 2).

| Intervention and intervention regimen
All trials used roasted peanut flour, three using AR101 29,31,32 and one measuring and reporting specific Ara antigens (Table 3). 29 All initial doses and dose increases were performed in clinical settings except for one study where the site and quantity of first day dosing and up-dosing were not clear. 11 First day dose The three trials using AR101 29,31,32 gave escalating doses over the first day, building from 0.5 to 6 mg peanut protein. One trial escalated from 0.1 to 6 mg 27 and one from 0.1 to 12 mg peanut protein. 26 One study commenced with a dose of 2 mg 28 and one titrated the initial dose to the food challenge eliciting dose (giving between 0.5 and 30 mg). 30   All intervention trial arms experienced more adverse effects than control arms. In the non-blinded studies with no placebo, food reactions (apart from severe reactions/anaphylaxis) in the control group were not recorded (as they were receiving no control intervention). Thus, we were not able to meta-analyze adverse reactions for studies with no placebo group.
Meta-analysis of any child having an allergic event from the seven double blind placebo-controlled studies found a risk ratio of any allergic reaction for the intervention (compared to placebo) of

| Overview of studies
There were six RCTs of hen's egg OIT 24 25,33,34 and one study determined a reaction threshold to customize OIT. 35 One study was restricted to a severely allergic group. 34 Of the six RCTs, three excluded children with a history of severe anaphylaxis following egg ingestion or anaphylaxis at egg challenge 25,33,35 ; three excluded children with poorly controlled or severe asthma [34][35][36] ; two excluded children with severe eczema 35,36 ; two excluded children sensitized to foods other than egg 24,34 ; one excluded children with symptoms of esophagitis 36 ; and two listed ability and/or willingness of families/participants to comply with the intervention as an inclusion criterion. 33,34,37 From the three studies 34-36 that provided a detailed breakdown, 12% (26/215) of the screened participants tolerated egg at the initial DBPCFC (Table 2).

Randomization and blinding
All studies used computer algorithms to randomize participants. In one study, 24 participants and investigators were blinded to the intervention with controls receiving corn flour. 24 In the remainder, control groups practiced egg avoidance.

Allergic adverse events
One placebo-controlled egg trial found that the risk ratio for children experiencing any allergic events was 9.17 in the intervention compared to the control group (95% CI 0.55, 152.78) ( Table 1 and NNT (adrenaline use) was not calculated as none of the children in the control groups were administered adrenaline.

| Overview of studies
Four trials 38-41 investigated cow's milk OIT: two from USA, 40,41 one from Japan, 38 and one from Italy (Table 1). 39 The number of participants varied from 20 40 to 30 39 with 106 in total. The average age of children ranged from 5.5 38 to 9.5 [39][40][41] years. Three studies excluded children with severe or uncontrolled asthma, 38,40,41 three excluded children with previous severe anaphylaxis, 38,40,41 two excluded children with other food allergies 38,39 and two excluded children with severe atopic dermatitis. 38,41 The initial DBPCFC was passed by 18% (17/94) of those screened (where information was available) Table 2.

| Intervention regimen
Two trials used whole cow's milk 38,39 initially diluted with water, and one used non-fat milk powder (Table 2). 40 One study 41

| Randomization & blinding
In three studies 39,40 participants were blinded to the intervention with control groups receiving soy milk, 39 maltodextran 40 or tapioca flour. 41 Control participants in the remaining studies practiced avoidance. None of the studies investigated remission.

| Allergic adverse effects
From two placebo-controlled studies 39,41 where information was available, the pooled estimate of any allergic reaction for those taking the intervention was RR. 3.75; 95% CI 0.28, 49.93 I 2 0% (Figure 3).

F I G U R E 5
Oral immunotherapy and adrenaline use.   (Figure 4).

| Risk of bias of included studies
Most studies were considered at low risk of bias with some being unclear concerning randomization procedures and one having excess loss to follow-up ( Efficacy must be balanced with the rate of allergic events. Although allergic reactions were generally mild and easily managed, most children receiving the intervention had an allergic reaction, and many had repeated reactions. To bring the evidence from all included studies together, we reported the proportion of subjects experiencing reactions. However, this is a crude measure of safety. Exposure adjusted incidence of adverse events (AE) is more meaningful as it describes the frequency or burden of AEs and offers a more precise measure of safety. In this review, we found OIT was associated with parenteral adrenaline use for every 20 patients treated with peanut OIT.
It is concerning that in four of the eight included peanut OIT trials there were between one and three diagnosed cases of eosinophilic oesophagitis (EoE) (total 6 across 4 trials). A 2014 metaanalysis 42 identified that EoE may occur in up to 2.7% of those undergoing OIT. A more recent, systematic review 13  Whether QoL is improved by OIT is an important part of the decision for undertaking OIT. Three of our included studies 26,31,35 investigated changes in QoL. One placebo-controlled study 31 of peanut OIT found improvements in all domains of self-reported and food allergy quality of life. However, unblinding was performed just prior to the second QoL assessment, which may have influenced responses. A more recent placebo-controlled study found good evidence in the improvement of QoL in the treatment group. 26 The third study 35 which compared intervention to avoidance, found increased QoL in those receiving OIT. Other QoL research has produced mixed findings. 16,17 The goals of OIT may differ depending on the individual child, their number of food allergies and their degree of reactivity or threshold dose for reaction. Although patients and physicians want a long-term solution such as remission of food allergy, families of food allergic children may have more modest goals including the desire to reduce the likelihood of anaphylaxis in the case of inadvertent ingestion of trace amounts of allergen, or to tolerate small amounts of the allergen that might be encountered through trace contamination of food products. 45 The strength of our approach is that we performed a high-quality objective process to choose the best RCTs to provide the most accurate evidence. However, this limited our studies to small, highly select populations. Populations included in RCTs are often not representative of the intended target population. Typically, most participants included in the trials did not have other food allergies, had not had a previous severe anaphylaxis, and did not have severe or uncontrolled asthma. Additionally, entry to many trials required highly supportive parents. The population of food allergic individuals included in these RCTs may be very different from the population in which the proposed treatment is to be applied. Therefore, the efficacy found in these trials may not be the same as the possible effectiveness that could be achieved in a real-world population of food allergic children. Furthermore, the rate and outcomes of adverse allergic events experienced during OIT may differ in families that are not as highly motivated to complete OIT and follow safety guidelines. In addition, study regimens were highly heterogenous and the overall number of participants was relatively low. Despite this, there was little statistical heterogeneity when studies were pooled in meta-analyses.
More research is needed with standard interventions and regimens to provide greater certainty around the efficacy and safety of OIT and to understand how to achieve and maintain greater levels of remission. 46 Further research should address the risks of eosinophilic esophagitis and whether the risk is greater for specific children, and whether OIT risks can be mitigated by concurrent immunomodulatory agents or probiotics. 26,47 We also need further understanding of the impact of OIT on QoL for food allergic children and their families.

| CONCLUSION
This systematic review of high-quality RCTs found that OIT had good efficacy in inducing desensitization and some efficacy for remission despite considerable heterogeneity in study methodology. We also confirmed that allergic events occurred frequently during OIT. Participants included in these RCTs are not representative of the entire food allergy population and care must be taken applying these findings to other populations where both efficacy and adverse effects may differ. Decisions around undertaking OIT need to be informed by consideration of individual circumstances.